4-Aryl-5-aminoalkyl-4-oxazolin-2-ones

ABSTRACT

represents a secondary or tertiary amino residue, Z represents an oxygen or sulphur atom, or an imino group, and R3 represents a hydrogen atom or a lower alkyl, a lower free or etherified hydroxyalkyl, an arylalkyl, a dialkylaminoalkyl, a lower aliphatic acyl, a lower aromatic acyl or a carbamoyl radical are provided with depressive or stimulative activity on the central nervous system, with hypotensive, muscular relaxing properties, which inhibits aggregation of platelets and which is antiarrhythmic and antihistaminic.   or a pharmaceutically acceptable salt thereof, in which Ar represents a mono or polycyclic, substituted or unsubstituted, aryl radical, Alk represents a linear or branched saturated or unsaturated hydrocarbon radical of one to three carbon atoms,   A class of 4-aryl-5-aminoalkyl-4-oxazolin-2-ones having the general formula:

United States Patent [191 Manghisi et al.

[ Dec. 30, 1975 4-ARYL-5-AMINOALKYL-4-OXAZOLIN- 2-0NES [75] Inventors:Elso Manghisi; Giuseppe Cascio,

both of Monza, Italy [73] Assigneez. Istituto Luso Farmaco dltaliaS.r.l.,

Milan, Italy 22 Filed: Oct. 3, 1973 211 App]. No.: 403,275

[30] Foreign Application Priority Data Oct. 16, 1972 Italy 30536/72 Aug.22, 1973 Italy 28115/73 [52] US. Cl. 260/268 PH; 260/243 B;

260/247.l M; 260/247.2 A; 260/247.2 B;

[51] Int. Cl? C07D 295/12 [58] Field oi Search 260/268 [56] ReferencesCited UNITED STATES PATENTS 3,576,808 4/1971 Schut 260/268 PH PrimaryExaminer-Donald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent,or Firm-Stevens, Davis, Miller & Mosher [57] ABSTRACT A class of4-aryl-5-aminoalkyl-4-oxaiolin-2-ones having the general formula:

or a pharmaceutically acceptable salt thereof, in which Ar represents amono or polycyclic, substituted or unsubstituted, aryl radical, Alkrepresents a linear or branched saturated or unsaturated hydrocarbonradical of one to three carbon atoms,

represents a secondary or tertiary amino residue,

1 Claim, No Drawings "In-this formula Ar represents amono-"orpolycarbocyclic-aryl group, is especially-a monocarbocyclic aryl groupsuch as phenyl or substituted phe 'nyL'which may have one or more of thesameor different substituents. Suitable substituents include loweralkyl, for example methyl, ethyl, n-propyl and isopropyl,trifluoromethyl, lower alkoxy, for example, methoxy, ethoxy, npropyloxy,isopropyloxy and n-butyloxy, lower alkeneoxy, for example 'vinyloxy andallyloxy, lower alkylenedioxy, for example methylenedioxy, halogen, forexample fluorine, chlorine or, bromine, alkylmercapto, for examplemethylmercapto or ethylmercapto, nitro, amino, i ncludingflower'N,N-dialky'lamino, for example N,N-dir nethylamino or N,N- diethylamino.The carbocyclic arylradical may also be a bicyclic radical such asnaphthyl, l-naphthyL' 'or Z-naphthyl, or substituted naphthyl', whichsubstituents can be the same'or different such as alkylnaphthyl,trifluoromethylnaphthyl, alkbxynaphthyl, alkeneo'xynaphth'yl,halogenonaphthyl or aminonaphthyl.

All; represents a linear -or branched saturated -or unsaturatedhydrocarbon radical comprising 1 to 3 carbon atoms. I

represents -a substituted or unsubstituted amino group in :which thesubstituents may be, especially; hydrogen atoms or loweralkyl,-'carbocyclic monocyclic aryl, particularly phenyl,monocarbocyclic arylalkyl, particularly phenylalkyl.

The N-monosubstituted amino groups may thus be for example,N-alkylamine, for example methylamino, ethylamino or propylamino,N-cycloalkylamino, for example N-cyclohexylamino, N-hydroxyalkylaminofor example N-2-hydroxyethylarnino, N-arylalkylamino, for-example benzylamino, Nfdialkylaminoethylamino, for example N,N-diethyleneciiamino,N-arylamino, forexample N-ph'er'rylami no or substituted N-phenylamino'z' 'The -N,N-disu'bstituted amino groups may be,- forexample, 1N",N-dialkylam ino, for example N,N-dimethylamino,N-methyl-N-ethylamino, N,N-diethylamino,' N,N-di-n-propylamino, w N,N-diisopropylamino' or N-methyl-diethylaminoethylamin'o, andN-cycloalkyl-N-alkylamino inwhich the cycloalkyl has from 3 to 8 atoms,for example N-cyclopentyl-N- methylamino orN-c'yclohexyl-N-ethylamino,-N-lower alkyl-N-phenylalkylamino, forexample N-benzyl-N- methylamino or N-ethyl-N'-phenylethylamino,= or any2 other disubstituted amino group such as N-hydroxyalkyl-N-alkyl-aminoinwhich the hydroxyl is separated from the nitrogen by at leasttwo carbonatoms, for example N-ethyl-N-(2-hydroxyethyl)amino, or N,N-dihydroxyalkylamino, for example N,N-di(2-hydroxyethyl)amino.

The radical imino, in which the alkylene preferably has four carbonatoms, for example 4-thio-morpholine, or N,N azaalkylene-imino in whichthe alkylene has from 4 to 6 carbon atoms and in which the aza nitrogenmay be substituted by, for example, lower alkyl, for example methyl,ethyl or propyl, lower hydroxyalkyl, for example hydroxyethyl, loweralkoxy alkyl, for example methoxyethyl, lower alkoxyloxyalkyl, forexample acetoxyethyl, lower arylalkyl for example benzyl,diphenylmethyl, 2'-phenyle'thyl, *2-3 '-indol'yl-ethyl,' or amonocarbocyclic aryl, preferably phenyl, unsubstituted or substitutedwith halogen atoms or alkyl, lower'alkoxy or nitro .groups, for examplephenyl, 2-tolyl, '2,3-xylyl, 4-

chlorophenyl or 2-methoxyphenyl or, finally, a heterocyclicmonocarbocyclic aryl, for example 2-pyridino, 2-furano or 2-thiopeno,such as pipe'razino, 4-methyl-l piperazin'o, 4-ethyl'- l -piperazino,-"4-'( Z-hydroxyethyl l-piperazino, 4-(2-acetoxyethyD-l-piperazino,4-be'n-" z'yll -piperazino, 4=(2'- 3 '-indolyl)-ethyll piperazi no,

4,2" metlioxyphenyl l-pipera ino, 4,2' pyri dyl-lpiperaiino or4,3'-pyridyl-l piperazino. Z represents an atom of oxygenorsul'phu roranimino group, In this latter case the compound'is generallyinfequilibrium with the corresponding tautomeric 2 far'jnino-oxazole Rrepresents a hydrogen atom oiia linear 'or branched lower alkyl, forexample methyLet'hyLprbpyl, or isopr'opyhbra'free'or etherifie dlowerhydroxy alkyl, for example "2-hydroxyethyl, 3 -hydroxypropyl,2-methoxyethyl, 3-methoxypropyl or 2'- hydroxyethoxyethyl, an arylalkyl,for example benzyl, a dialkylamino alkyl, for exampleN,N-diethylaminoethyl, or a lower aliphatic acyl, for example acetyl,propionyl, carbamoyl, N-alkylcarbamoyl, N-phenylcarbamoyl,N-alkylthiocarbamoyl or N-phenylthiocarbamoyl, or an aromatic acylunsubstituted or substituted with halogen atoms, or methoxy groups, forexample benzoyl, p-chlorobenzyh; p-methoxybenzoyl or3,4,5-trimethoxybenzoyl. The invention also relates to processes forpreparing the substances of general formula (I).

The compounds of the present invention, with the exception of thosewhich carry substituents which can interfere with the reactingcompounds, can be prepared by reacting compounds of general formula ll:

. /Rl ArCO-iHAlk-N (ll) in which, Ar, Alk and have the meanings givenabove, with phosgene, thio p'hosgene, ethyl chlorocarbonate, or ethylcarbonate and then with an amine of formula: R NH in which R has themeanings given above, generally in the presence of a proton acceptorsuch as triethylamine or dimethylanilin'e and in a non-polar solvent,such as chloroform, benzene or toluene and at a temperature between lCand +50C.

The substances of formula (Ill) are formed as intermediate products Iwhich either spontaneously or, by, generally hot, treatment with organicor inorganic acids such as glacial acetic acid, dilute mineral acids orp-toluene-sulphonic acid or other dehydrating agents give the compoundsof formula I. v I

The products of the present invention can also be obtained by reactingthe products of formula II, suitably .in the molten state, with analkylisocyanate, arylalkylisocyanate, arylisocyanate, alkylurethane,carbamoylchloride, or alkyl isothiocyanate, followed by acid treatment.The products of general formula I can also be obtained by reacting thecompounds of general formula ll with isothiocyanic acid, generally underhot conditions in the presence of solvents, or with cyana; mide,generally under hot conditions in a hydroalcoholic environment.

Another method of preparing the products of the present inventionconsists of reacting the compounds of formula IV, generally under hotconditions in a non polar solvent such as benzene, toluene or xylene,

in which Ar, Alk, R and Z have the meanings given above and Y representsa halogen atom or a tosyl radical, with an amine of formula:

Finally the products of general formula I in which R is not a hydrogenatom'can' be obtained from the corresponding compounds in which Rrepresents a hydrogen atom, by alkylation or acylation, for exampleafter preparing the sodium salt, with compounds of general formula R Xin which R is as defined above and X represents a halogen atom, a tosylradical or the acyl residue of a mixed anhydride.

Suitable alkylating agents include oxides of ethylene and propylene andsuitable acylating agents include isocyanates of formula R NCO in whichR represents a lower alkyl group, for example methyl, ethyl, propyl orbutyl or a monocarbocyclic aryl group, for example phenyl, or thecorresponding isothiocyanates of general formula R NCS.

A further method for preparing products of general formula I in whichRrepresentsa hydrogen atom consists of reacting, suitably under hotconditions, compounds of general formula V with ammonium acetate in thepresence of acetic acid.

The compounds of general formula ll can be prepared as described inItalian Pat. Application No. 23444 A/72 f led 22.41972. Generallycompounds of general formula VI: I Y

Ar--CO CH-Alk Y (VI) in which X andY represent halogen atoms, arereacted with alcoholates of alkali metals or alkaline earth metals, andthen with amines of formula The intermediate products of general formulaIV can be obtained by reacting the compounds of general formula Vl withalkaline alcoholates followed by acid hydrolysis to give intermediatesof the presumed formula which are then subjected to ring closure to givethe oxazolinones by the methods given above.

Salts of the compounds of general formula l can be prepared withpharmaceuticallyacceptable inorganic acids, for example hydrochloric,hydrobromic, nitric, sulphuric and phosphoric acids, and with organiccarbonyl acids, for example acetic, propionic, glycolic,

-continued Comp- Stereotype-rat Vomit-Dog Catalepsy Shock-mouseConditioned reflexesounds mg/Kg/bw per os mg/Kg/bw mg/Kg/bw per osmg/Kglbw per os rat mg/Kg/bw per os Amphetamine Apomorphine Apomorphinemouse rat triptam'ine Avoidance DW per os LR 504 56 =50% 50 50% 28.2 50%LR 522 100 50% 47 50% LR 503 100 50% 200 50% 50 33% 63 50% 8.2 50% 16.4

50% LR 533 75=50% 1l2=50% 75 =50% 13.2=50% 100=94% LR 512 24.1 =50%75=50% 75=50% =50% LR 513 200 50% 200 50% LR 516 100=40% 25 =50% =50% LR502 150 40% 150 40% 37.5 50% 19 50% LR 514 18.5 50% 44 50% 2.5 50% 18.550% 30.5 50% 8.3 50% 4.4 50% 4.5 50% LR 515 90=30% 150=40% 9=50% 75= 13%25=50% LR 534 30 13% LR 542 200 23% LR 552 200 30% 120 50% LR 553 9.550% 180 30% 47 50% 6.8 50% LR 567 LR 583 LR 585 11.4 50% 14.5 50% 25 50%30 50% 4 50% Compounds Aggressivity-mouse Strengthening of barbituricLethality Noradrenalin-mouse mg/Kg/bw per os sleep-mouse mg/Kg/bw per osmg/Kg/bw per os LR 466 8 50% 33 50% 50% LR 511 3=50% 41 =50% 17.9=50% LR496 LR 504 10 20% 27.5 50% 100 50% LR 522 60 50% LR 503 10 30% 86 50%100 50% LR 533 10 60% 76.5 50% 200 10% LR 512 40 50% 30% LR 513 l00=50%=20% LR 516 70 50% LR 502 99 50% 75 50% LR 514 4 50% 9.1 50% 37.5 50% LR515 I =50% 75=40% LR 534 LR 583 LR 585 5 50% 45 EXAMPLE 14-p-fluorophenyl-S-B-(4-phenyl-piperazino)-ethyl-4- oxazolin-2-oneCompounds DL SO-mouse Arrhythmia Isolated To 35 cc. of a 20% solution ofphosgene in toluene, 8 1 l 5o agitated and cooled to 0C, are added over30 minutes mg/Kg/iv rabbit (lntra- /ml a solution of 20 g ofl-p-fluoro-benzoyl-1-hydroxy-3-N- venmlsly) (N'-phenyl)piperazino-propane and 7.3 g of trieth yl- 496 75 50 50% amine in 200 ccof anhydrous chloroform. It is agitated ggi 1 28 3 7 50% ;8 f 283 atambient temperature for 5 hours, cooled to 0C and 576 50% lo 55thesolution saturated with gaseous ammonia. The solu- 577 30 50% tion isagitated at ambient temperature for 3 hours, 22? 58 Z283; I filtered andthe filtrate dried under reduced pressure. 583 350 I4 50% m.p. 192C (byalcohol) Similarly the following are prepared: 604-p-fluoropheny1-5-B-(4-o-methoxyphenyl- The following Examples furtherillustrate the present piperazino)-ethy1-4-oxazolin-2-one m.p. 154Cinvention. The melting and boiling points are not cor- (by alcohol)rected. 4-p-fluorophenyl-5-N-piperidinoethyl-4-oxazolin- The identity ofthe substances and their purity have 2-one maleate m.p. 272C (byalcohol) been ascertained by elementary analyses of carbon, 654-p-chlorophenyl-S-B-(4-phenyl-piperazino )-ethylhydrogen, and nitrogen(and halogens where present), 4-oxazolin-2-one m.p. C (by alcohol)infrared specta, N.M.R. (nuclear magnetic resonance)4-p-methoxyphenyl-5-B-(4-phenyl-piperazino)- and U.V. (ultra-violet).ethyl-4-oxazolin-2-one m.p. 188C (by alcohol) '4-p fluorophenyl-5diethylaminoethyl-4.-oxazolin- 2-onemaleate mip. 153C (byalcohol)4-p-fluorophenyl-5-((4-benzamido-piperazino)- ethyl)-4.-oxazolin-2-onem.p. 229C (by alcohol)4-p-fluorophenyl-5-B-(4-pyridyl)-piperzino)-ethyl-4- 'oxazolin-2-o'nem.p. 172C (by; alcohol) 4-p-fluorophenyl-5-( (4-p-chloropheny1)-1 ,2,3,6-tetrahydropyridino) ethyl)-4-oxazolin-2-one m.p. 205C (by alcohol)4-p.fluorophenyl-5 (N-methyl-phenethylamino ethyl)-4-oxazolin-2-onemaleate.m.p. =.155C (by alcohol) n 1. 4-p-fluorophenyl-5('N-methyl-diethylaminoethylamino)-ethyl)-4-oxazolin-2-one dimaleatem.p. 149C. (by alcohol) 4-phenyl-5-diethylaminoethyl-4-oxazolin-2-onemaleate m.p. 159C (by' alcohol)4-p-fluorophenyl-5-B-(4-methyl-piperazino )-ethyl-4- oxazolin-2-one m.p.159C (by alcohol) Similarly, by substituting the ammonia with theappropriate amines, the following are. prepared:3-methyl-4-p-fluorophenyl-5-B-(4-phenylpiperazino)-ethyl-4-oxazolin-2-onem.p. 104C (by alcohol) 1 3ethyl-4-p-fluorophenyl-5-B-(4-phenyl-piperazino ethyl-4-oxazolin-2-onem.p. 85C (by alcohol) 3-benzyl-4-p-fluorophenyl-5-B(4-phenylpiperazino)-ethyl-4-oxazolin-2-one m.p. 120C '(by alcohol)3-diethylaminoethyl-4=p-fluorophenyl-5-B (4- phenyl)-piperazino-ethyl-'4-oxazo1in-2-one m.p. 71C (by hexane)3-diethylaminoethyl-4-p-fluorophenyl-5 diethylaminoethyl-4-oxazolin-2-one b.p. 186C at 0.6Torr. f The1-aroyl-1'-hydroxy-3-aminopropanes are prepared as described in theItalian Patent Application No. 23444 A/72 filed 22.4.1972.

. EXAMPLE'Z 4-phenyl-5-B-(4-phenyl piperazino)-ethyl-4-oxazolin- 2-o neI A solution of 7.5 gof 4-phenyl-5-chloroethyl-4- oxazolin-2y-one, l ;8g of N-phenyl-piperazine, and catalytic quantities of potassiumiodide.(l(l). in 150 cc. of toluene is agitated for 20 hours. It isfiltered and the filtrate extracted with dilute HCl. The aqueous phaseis rendered alkaline with ammonia. The precipitated solid is filtered;m.p. 188C (by alcohol). The 4-phenyl-5-chloroethyl-4-oxazolin-2-one isprepared in the following manner: to 65 cc. of a solution of phosgene intoluene, agitated and cooled to 0C, are added over 20 minutes a solutionof 21.3 g of l-benzoyl-lhydroxy-3'chloropropane, and 14.3 g oftriethylamine in 200 cc of anhydrous chloroform. It is agitated for 6hours at ambient temperature, cooled to 0C, and saturated with gaseousammonia. lt is left under agitation for a further 3 hours at ambienttemperature and then filtered. The filtrate is dried and the residuedissolved in benzene, washed with water and dried over Na SO andevaporated to dryness. The residue is used for the reaction withoutfurther purification.

The 1-benzoyl-l-hydroxy-3-chloro propane, as described in the ItalianPatent Application No. 23444 A/72 filed 22.4.1972 is prepared in thefollowing manner: to a solution of sodium methylate, obtained by g 1.0;dissolving 3.52 g of sodium, in 130 cc. of absolute methanol, are added,all at once, at ambient temperature, 4O g of l-benzoyl-l-bromo-3-chloro-propane (prepared from l-benzoyl-3-chloro propane withbromine in acetic acid) dissolved in cc. of absolute methanol. l f

The reaction mixture is left by itself for 3 days. The solvent iseliminated at reduced pressure and the residue is dissolved indiethylether and filtered. The filtra'te, when evaporated to drynessunder vacuum, gives an oily residue which is mixed with 100cc. of dilutehydrochloric acid and maintained at 50C for 30 minutes under agitationand then cooled. The product is then extracted with benzene and theorganic phase separated, washed with water until neutral and dried overNa SO for 2 days. 3 s

The solution is filtered, the filtrate is evaporated to dryness undervacuum and the oily residue is used directly for the reaction.

EXAMPLE 3 3 butyl 4-p-fluorophenyl 5-B(4-phenyl-piperazino)-ethyl-4-oxazolin;2-'one A mixture of 10 g of1-p-fluorobenzoyl-l-hydroxy-3- N-(N-phenyl)-piperazino-propane and 3.5 gof butylisocyanate is heated in the moltenstate at 100C for 2 hours andthen cooled. The reaction mass is dissolved in benzene and filtered hotwith animal charcoal. On adding hexane to the filtrate, a white solidprecipitates which is recrystallised from alcohol and filtered. Thesolid is agitated in cc. of acetic acid for 4 hours and the hot solutionfiltered with animal charcoal. The filtrate is dried under reducedpressure and the residue, dissolved in benzene, is washed with a dilutesoda solution and then with water. The benzene phase isdried andevaporated to dryness under reduced m.p. 7 1C (by alcohol). Thefollowing arejsimila rly prepared: I

3-butyl-4-p-fluoropheny1-5-( l -(4'-hydroxy-4-(pchlorophenyl)piperidino)-ethyl)-4-oxazolin 2-one m.p. 72C (by alcohol)3-methyl-4-p-fluorophenyl-5-diethylaminoethyl-4- oxazolin-2one-citratem.p. 90C (by alcohol) 3-phenyl-4-p-fluorophenyl-5-B (4-phenyl- Ipiperazino)-ethyl 4-oxazolin 2-one m.p. C

(by alcohol) v EXAMPLE 4 ethyl-4-oxazolin-2-one A suspension of 7.5 g of4-p-fluorophenyl-5-B-(4- phenyl-piperazino)-ethyl-4-oxazolin-2-one, 17.4cc. of acetic anhydride and 1.63 g of anhydrous pyridine is heated overan oil bath at 130C for 3 hours. The reaction mixture is evaporated todryness under vacuum and the residue, dissolved in benzene, is washedwith water. The dried benzene phase is evaporated to dryness at reducedpressure.

' m.p. 107C (by hexane) Similarly the following are prepared:

3-acetyl-4-p-fluorophenyl-5-diethylaminoethyl-4- oxazolin-2-one b.p. Cat 0.6 Torr.

3-acetyl-4-p-fluorophenyl-5-B-(4-o-methoxyphenylpiperazino)-ethyl-4-oxazolin-2-onehydrochloride. m.p. 222C (by alcohol)3-benzoyl-4-p-fluorophenyl-5-B-(4-phenylpiperazino)-ethyl-4-oxazolin-2-onehydrochloride. m.p. 233C (by alcohol) EXAMPLE3-methylaminocarbony1-4-p-fluorophenyl-S-B-(4-phenyl-piperazino)-ethy1-) 4-oxazolin-2-one hydrochloride.

A mixture of 4 g of 4-p-fluorophenyl-5-B-(4-pheny1-piperazino)-ethyl-4-oxazolin-2-one and 4.16 g of methylisocyanate isheated in a closed tube at 140C for 90 minutes.

The reaction mass is treated with alcoholic hydrochloric acid m.p. 209C(by alcohol) EXAMPLE 6 4-p-fluorophenyl-5-B-(4-o-methoxy-phenylpiperazino )-ethyl-4-oxazalin-2-thione A mixtureof 2 g of 1-p-fluorobenzoyl-1-hydroxy-3N-(N'-o-methoxyphenyl)-piperazino-propane, 1.7 g of potassiumisothiocyanate, and 1 cc of concentrated HCl in 40 cc. of ethanol isrefluxed for a total of 40 hours.

The solution is concentrated to half volume, cooled and the precipitatedsolid filtered and dried. The solid is suspended in water, and thesuspension, rendered alkaline with ammonia, is extracted with benzene anumber of times. The benzene phase, dried and evaporated at reducedpressure, gives a solid.

m.p. 180C (by alcohol) The following is similarly prepared:

' 4-p-fluorophenyl-5-B-(4-pheny1-piperazino)-ethyl-4- oxazolin-2-thione. m.p. 170C (by isopropyl alcohol) EXAMPLE 7 4-p-fluoropheny1-5-B-( 4-pheny1-piperazino )-ethyl-2- imino-oxazoline A solution of 5 g ofl-p-fluorobenzoyl-l-hydroxy-3- N(N'-pheny1)-piperazinopropane, 0.83 g ofcyanamide, 10 cc. of H 0 and 160 cc. of ethanol is refluxed for a totalof 40 hours. The solvent is removed at reduced pressure. m.p. 192C (byalcohol).

EXAMPLE 84-p-fluorophenyl-5-B-(4-o-methoxyphenyl-piperazino)-ethyl-imino-oxazoline-Z-imino-oxazolineA mixture of 12 g of 4-p-fluoropheny1-5-chloroethy1- 2-imino-oxazolinehydrobromide and 21.4 g of omethoxyphenylpiperazine in 200 cc. oftoluene is rea r t 12 fluxed for a total of 28 hours. The solid presentis filtered and the filtrate is washed a number of times with water andthen dried over Na SO The solvent is removed at reduced pressure. m.p.210C (by alcohol). The 4-p-fluorophenyl-5-ch1oroethy1-2-imino-0xazolinehydrobromide is prepared in the following manner:

20 g of 1-p-fluorobenzoyl-l-bromo-3-chloropropane, 21.6 g of urea and 50cc. of dimethylformamide are heated for 45 hours at C.

The solvent is removed at reduced pressure and the residue is treated anumber of times with diethyl ether and finally with acetone, filteredand used for the reaction without further purification.

We claim:

1. A 4-aryl-5-aminoalkyl-4-oxazolin-2-one selected from the groupconsisting of 4-p-fluoropheny1-5-B-(4- phenylpiperazino)ethyl-4-oxazolin-2-one,4-pfluorophenyl-S-B-(4-o-methoxy-phenylpiperazino)ethyl-4-oxazolin-2-one,4-phenyl-5-B-(4- phenyl-piperazino)-ethy1-4-oxazolin-2-one,4-pchlorophenyl-S-B-(4-pheny1-piperazino) ethyl-4- oxazolin-Z-one,4-p-methoxy-phenyl-5-B-(4-phenylpiperazino) ethyl-4-oxazolin-2-one,3-methy1-4-pfluorophenyl-S-B-(4-phenyl-piperazino) ethyl-4-oxazo-1in-2-one, 3-ethyl-4-p-fluoropheny1-5-B-(4-pheny1- piperazino)ethyl-4-oxazolin-2-one,3-butyl-4-pfluorophenyl-S-B-(4-pheny1-piperazino)ethy1-4-oxazolin-2-one, 3-benzyl-4-p-fluoropheny1-5-[3-(4-pheny1-piperazino) ethyl-4-oxazolin-2-one,3-diethyl-aminoethyl-4-p-fluorophenyl-5-B-(4-phenyl-piperazino)ethy1-4-oxazolin-2-one, 3-acetyl-4-p-fluorophenyl-5-B-(4-phenyl-piperazino) ethyl-4-oxazolin-2-one, 3-benzoy1-4-p-fluoropheny1-5-B-(4,-pheny1-piperazino) ethyl-4- oxazolin-2-one,4-p-fluorophenyl-5-/3-[4-(2 pyridy1)- piperazino]ethy1-4-oxazo1in-2-one, 4-p-t'luoropheny1- 5-B-(4-methy1-piperazino)ethyl-4-oxazo1in-2-one, 3-pheny1-4-p-fluorophenyl-5-B-(4-phenyl-piperazino)ethy1-4-oxazo1in-2-one,3-methy1amino-carbony1-4-pfluorophenyl-S-B-(4-phenyl-piperazino)ethyl-4-oxazo- 1in-2-one,3-acetyl-4-p-fluorophenyl-5-B-(4-o-methoxyphenyl-piperazino)ethyl-4-oxaiolin-2-one,4-pfluorophenyl-S-B-(4-pheny1-piperazino )ethyl-4-oxazo- 1in-2-thione,4-p-fluorophenyl-5-B-(4-o-methoxyphenyl-piperazino)ethy1-4-oxazolin-Z-thione,4-pfluorophenyl-5-B-(4-pheny1piperazino) ethyI-Z-iminooxazoline,4-p-fluoropheny1-5-B-(4-o-methoxyphenylpiperazino)ethyl-2-imino-oxazoline,and a pharmaceutically acceptable salt thereof.

1. A 4-ARYL-5-AMINOALKYL-4-OXAZOLIN-2-ONE SELECTED FROM THE GROUPCONSISTING OF 4-FLUOROPHENYL-5-B-(-4-PHENYLPIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE,4-P-FLUOROPHENYL-5-B-(4O-METHOXY-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE,4-PHENYL-5-B-(4-PHENYL-PIPERAZINO)-ETHYL-4-OXAZOLIN-2-ONE,4-PCHLOROPHENYL-5-B-(4-PHENYL-PIPERAZINO) ETHYL-4-OXAZOLIN2-ONE,4-P-METHOXY-PHENYL-5-B-(4-PHENYL-PIPERAZINO) ETHYL4-OXAZOLIN-2-ONE,3-METHYL-4-P-FLUOROPHENYL-5-B-(4-PHENYLPIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE,3-ETHYL-4-P-FLUOROPHELYL5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE, 3-BUTY-4P-FLUOROPHENYL-5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2ONE, 3-BENZYL-4-FLUOROPHENYL-5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN:2-ONE,3-DIETHYL-AMINOETHYL-4-P-FLUOROPHENYL-5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE,3-ACETYL-4-P-FLUOROPHENYL-5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE, 3-BENZOYL-4-P-FLUOROPHENYL-5-B-(4PIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE, 4-P-FLUOROPHENYL-5-B-(4(2 PYRIDYL)-PIPERAZINO)ETHYL-4-OXAZOLIN -2-ONE, 4-PFLUOROPHENYL-5-B-(4-METHYL-PIPERAZINO)ETHYL-4-OXAZOLIN2-ONE,3-PHENYL-4-P-FLUOROPHENYL-5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE,3-METHYLAMINO-CARBONYL-4-PFLUOROPHENYL-5-B-(4-PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN 2-ONE,3-ACETYL-4-P-FLUOROPHENYL-5-B-(4-O-METHOXYPHENYLPIPERAZINO)ETHYL-4-OXAZOLIN-2-ONE,4-P-FLUOROPHENYL-5-B-(4PHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2-THIONE,4-P-FLUOROPHENYL-5-B-(4-O-METHOXYPHENYL-PIPERAZINO)ETHYL-4-OXAZOLIN-2THIONE,, 4-P-FLUOROPHENYL-5-B-(4-PHENYLPIPERAZINO)ETHYL-2IMINO-OXAZOLINE,4-P-FLUOROPHENYL-5-B-(4-O-,METHOXYPHENYLPIPERAZINO)ETHYL-2-IMINO-OXAZOLINE,AND A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF.